Neuropeptides were studied as both regulators of activity-related neurodevelopment and as substances that were themselves regulated by electrical activity. Primary cell culture preparations from the mammalian central nervous system were employed. Vasoactive intestinal peptide was shown to act as a secretagogue for the following from rat cortical astrocytes: an interleukin-I-like substance and protease nexin I. A reversible down regulation of mRNA for VIP was observed in spinal cord cultures that were electrically blocked with tetrodotoxin. This activity-related gene regulation of VIP was attenuated with active phorbol ester or exogenous VIP. A novel antagonist to VIP, when administered to developing rats, was found to produce deficits in complex motor behaviors without delays in the occurrence of developmental milestones. Dystrophic neurons were observed within deep layers of cerebral cortex of developing rats which had been treated with the VIP antagonist. In mature rats, the VIP antagonist was shown to produce cognitive impairment as assessed by performance in the Morris water maze. The regional specificity for the antagonist was demonstrated in that VIP receptors located in lymph nodes, superior cervical ganglion, gut, lung and pancreas were not responsive, whereas those in spinal cord, hippocampus and cerebral cortex were potently inhibited. Northern blots of mRNA were probed with random-primed DNA from the alpha-2-D, alpha-2-A and alpha-1-B adrenergic receptor cDNAs. A unique regional and ontogenic expression was observed for these three subtypes of alpha receptors present in rat brain and other tissues.